Maria Josepha was terrified of dying of smallpox after the death of her older sister Archduchess Maria Johanna Gabriela in 1762, and sister-in-law Maria Josepha of Bavaria, second wife of her elder brother Joseph II, Holy Roman Emperor, in May 1767. Her fears were realized when she died of smallpox on the very day she was to have left Vienna for her journey across the alps to marry the King of Naples, Ferdinand I of the Two Sicilies. She contracted smallpox because her mother, Maria Theresa, insisted that she go and pray at the tomb of her sister in law, who had recently died of the disease. The tomb was improperly sealed and Maria Jospha caught the disease, dying three days later.
After her death, her sister Marie Caroline of Austria was given as a bride to the King of Naples in her place.